Heteroaromatic ring compounds as CDK7 kinase inhibitors and their preparation and use

Abstract

The present invention provides heteroaromatic ring compounds as CDK7 kinase inhibitors, as well as their preparation and use. The heteroaromatic ring compounds are compounds having the structure of Formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, solvates, or prodrugs thereof. The present invention also provides pharmaceutical compositions comprising compounds having the structure of Formula (I) or pharmaceutically acceptable salts, esters, stereoisomers, solvates, or prodrugs thereof. The present invention also provides the use of compounds having the structure of Formula (I) or pharmaceutical compositions in the preparation of CDK kinase inhibitors and in the preparation of drugs for treating and / or inhibiting CDK-related diseases. The CDK7 kinase inhibitor compounds of the present invention have superior enzymatic and cellular biological activity and lower cardiotoxicity than previously disclosed compounds of the same type. The compounds of the present invention provide more options for novel antitumor drugs and are expected to be used as drugs in the future.

Description

[Technical Field]

[0001] The present invention relates to a series of heteroaromatic ring structure derivative compounds and their use as CDK7 kinase inhibitors, particularly to compounds represented by formula (I) or pharmaceutically acceptable salts thereof: [Background technology]

[0002] Cyclin-dependent kinases (CDKs) belong to the serine / threonine kinase family. Their monomers are inactive and must bind to corresponding cyclins to form active heterodimeric complexes to exert their regulatory effects. They catalyze the phosphorylation of their corresponding substrates, directly or indirectly regulating cells to complete the cell cycle and inducing cell growth and proliferation. Currently, the human genome has been found to encode 21 CDKs and over 15 cyclins. Based on their functions, CDKs can be broadly divided into two types: those that regulate the cell cycle and those that regulate cellular transcription. Among these, CDK1 / 2 / 4 / 6 are primarily involved in the cell cycle, while CDK7 / 8 / 9 / 10 are primarily involved in the transcriptional mechanism of cellular genetic information.

[0003] CDK7 is an important member of the CDK family and regulates the cell cycle mainly in two indirect ways: CDK7, together with cyclin H and Matl, constitutes CAK (CDK activating kinase), which further phosphorylates CDKl / 2, thereby activating their functions in the cell cycle.

[0004] Alternatively, CDK7, as a subunit component of the general transcription factor TFIIH, phosphorylates the carboxy-terminal domain (CTD) of the large subunit of RNA polymerase II (RNAP II), regulating gene transcription in cells. CDK7 plays an important role in cell proliferation, cell cycle, and transcription through its dual functions of CAK and CTD phosphorylation.

[0005] In recent years, CDK7 inhibition has become a promising therapeutic strategy for multiple cancer types. CDK7 inhibition can block the expression of key oncogenic genes, such as c-Myc. Preclinical data suggest that small molecule inhibitors of CDK7 have demonstrated favorable anticancer effects in hormone receptor-positive and triple-negative breast cancers, as well as transcription factor-driven cancers, such as small cell lung cancer (SCLC), including the small molecule drug CT-7001 developed at Emory University. These cancers currently lack effective treatments, presenting significant unmet medical needs. Furthermore, due to their distinct mechanisms of action, CDK7 inhibitors are effective against cancers that have already developed resistance to current treatments. Therefore, the development of CDK7 inhibitors has great potential as an effective treatment for these malignancies. Summary of the Invention

[0006] An object of the present invention is to provide heteroaromatic ring compounds which are a type of CDK7 kinase inhibitor.

[0007] The object of the present invention can be achieved by the following means. A first object of the present invention is to provide a compound of the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof: [ka] In the formula, R1 is a substituted or unsubstituted deuterated C1-C3 alkyl group, a C1-C3 alkyl group, a C2-C6 olefin, a C2-C6 alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group; the substituents are independently selected from H, D, halogen, a hydroxy group, -CN, a carbonyl group, a C1-C3 alkyl group, a C1-C3 olefin or alkyne, a deuterated C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy C1-C3 alkyl group, a fluoro C1-C3 alkyl group, a cyano C1-C3 alkyl group, a C3-8 cycloalkyl group, a C3-10 heterocyclyl group, and a C6-10 aryl group; R2 is selected from halogen, a hydroxy group, -CN, a carbonyl group, a C1-C3 alkyl group, a C2-C6 olefin, a C2-C6 alkyne, a deuterated C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy C1-C3 alkyl group, a fluoro C1-C3 alkyl group, and a cyano C1-C3 alkyl group; When R1 is a benzyl group, R2 is -CN; Furthermore, R1 is a substituted or unsubstituted C1-C3 alkyl group, a C2-C6 olefin, a C2-C6 alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group.

[0008] Preferably, R2 is selected from -CN and C1 to C3 alkyl groups.

[0009] Furthermore, R1 may be a substituted or unsubstituted [ka] is.

[0010] Furthermore, the compound is [ka] Selected from.

[0011] Salts that the compounds of the present invention can form also fall within the scope of the present invention. Unless otherwise specified, the compounds of the present invention are understood to include their salts. For example, the compound of formula (I) can be obtained by reacting it with a certain amount, for example, an equivalent amount, of an acid or base, and precipitating the salt in a medium or lyophilizing it in an aqueous solution. The basic fragment contained in the compound of the present invention includes, but is not limited to, an amine, a pyridine, or an imidazole ring, and may form a salt with an organic or inorganic acid. Non-limiting examples of pharmaceutically acceptable salts of the compound of formula I include monohydrochloride, dihydrochloride, methanesulfonate, trifluoroacetate, and ditrifluoroacetate.

[0012] The compound of the present invention is obtained by sequentially producing, separating, and purifying the compound, and the weight content of the compound is 90% or more, for example, 95% or more, or 99% or more (a "highly pure" compound), as described in the description of this specification. Such a "highly pure" compound of the present invention is also included in the present invention.

[0013] A third object of the present invention provides pharmaceutical compositions comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, or prodrug thereof.

[0014] Additionally, the pharmaceutical composition may further comprise other therapeutic agents and / or a pharmaceutically acceptable carrier.

[0015] A fourth object of the present invention provides use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug, or pharmaceutical composition thereof in the manufacture of a CDK kinase inhibitor.

[0016] A fifth object of the present invention provides use of a compound having the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug, or pharmaceutical composition thereof in the manufacture of a medicament for treating and / or inhibiting a CDK-related disease.

[0017] Furthermore, the CDK-related disease is cancer.

[0018] The present specification further provides a method of inhibiting cell proliferation in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula I, as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0019] The present specification further provides a method of treating a CDK-related disease or condition in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound of formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0020] The present specification further provides a method of treating cancer and / or inhibiting cancer metastasis associated with certain cancers in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0021] The present specification further provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof for use in therapy.

[0022] The present specification further provides a compound of formula (I) as defined herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition thereof for treating cancer and / or inhibiting cancer metastasis associated with certain cancers.

[0023] The present specification further provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for inhibiting CDK kinase activity.

[0024] The present specification further provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, for the treatment of a CDK-related disease or condition.

[0025] The present specification further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined herein for use in the manufacture of a medicament for treating cancer and / or inhibiting cancer metastasis associated with certain cancers.

[0026] The present specification further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined herein for use in the manufacture of a medicament for inhibiting CDK kinase activity.

[0027] The present specification further provides the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as defined herein for use in the manufacture of a medicament for the treatment of a CDK-related disease or condition.

[0028] The present specification further provides a method for treating cancer in a patient in need thereof, comprising: (a) determining whether the cancer is associated with dysregulation of expression, activity, or level of a CDK gene, a CDK kinase, or any one thereof (e.g., a CDK-associated cancer); and (b) if the cancer is determined to be associated with dysregulation of expression, activity, or level of a CDK gene, a CDK kinase, or any one thereof (e.g., a CDK-associated cancer), administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof.

[0029] The present specification further provides a pharmaceutical combination for treating cancer (e.g., a CDK-related cancer, e.g., a CDK-related cancer with one or more CDK inhibitor-resistant mutations) in a patient in need thereof, the pharmaceutical combination comprising: (a) a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof; (b) an additional therapeutic agent; and (c) optionally at least one pharmaceutically acceptable carrier, wherein the compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are prepared in separate compositions or doses for simultaneous, separate, or sequential treatment of cancer, wherein the amounts of the compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are both effective to treat cancer. The present specification further provides a pharmaceutical composition comprising such a combination. The present specification further provides the use of such a combination in the manufacture of a medicament for treating cancer. The present specification further provides a commercial package or article of manufacture comprising such a combination, which is a combined formulation for simultaneous, separate, or sequential use, and a method for treating cancer in a patient in need thereof.

[0030] Further provided herein is a method for reversing or preventing acquired resistance to an anti-cancer drug, comprising administering to a patient at risk of developing or having acquired resistance to the anti-cancer drug a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the patient is administered a dose of the anti-cancer drug (e.g., essentially simultaneously with administering to the patient a dose of the compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof).

[0031] The present specification further provides a method for delaying and / or preventing the development of cancer resistance to an anti-cancer drug in an individual, comprising administering to said individual an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during or after administration of an effective amount of an anti-cancer drug.

[0032] The present specification further provides a method of treating an individual suffering from cancer and having an increased likelihood of developing resistance to an anti-cancer drug, the method comprising: (a) administering to the individual an effective amount of a compound of formula (I) before, during, or after administration of (b) an effective amount of an anti-cancer drug.

[0033] Further provided is a method of treating an individual suffering from a CDK-associated cancer that has one or more CDK inhibitor-resistant mutations that increase the resistance of the cancer to a first CDK inhibitor, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during or after administration of another anti-cancer drug.

[0034] Further provided is a method of treating an individual suffering from a CDK-associated cancer, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof before, during, or after administration of another anti-cancer drug (e.g., a first CDK kinase inhibitor).

[0035] The present invention further provides a method for preventing and / or treating tumors, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of formula I above, or a tautomer, stereoisomer or isotopic derivative thereof, or a pharmaceutically acceptable salt of either of the above, or a crystalline form or solvate of either of the above.

[0036] In some embodiments, the tumor may be breast cancer, ovarian cancer, small cell lung cancer, acute myeloid leukemia, acute lymphocytic leukemia, bladder cancer, colon cancer, prostate cancer, epithelial sarcoma, or soft tissue sarcoma.

[0037] In some embodiments, the patient is a human.

[0038] The compounds of formula (I) and their pharmaceutically acceptable salts and solvates are also indicated for the treatment of CDK-associated cancers.

[0039] The present specification further provides a method for treating a patient diagnosed or identified as suffering from a CDK-associated cancer (e.g., any one of the exemplary CDK-associated cancers disclosed herein), comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0040] The terms of the present invention are defined as follows unless otherwise specified. The term "halogen" refers to --F (sometimes referred to herein as "fluoro"), --Cl, --Br, and --I.

[0041] The term "deuterated C1-C3 alkyl group" refers to a saturated, straight- or branched-chain monovalent hydrocarbon group having one to three carbon atoms, in which one to three carbon atoms are replaced with deuterium. Examples include, but are not limited to, deuterated methyl, deuterated ethyl, deuterated 1-propyl, and deuterated isopropyl groups.

[0042] The terms "C1-C3 alkyl group," "C1-C6 alkyl group," "C2-C6 alkyl group," and "C3-C6 alkyl group" refer to saturated, straight- or branched-chain monovalent hydrocarbon groups having 1 to 3, 1 to 6, 2 to 6, or 3 to 6 carbon atoms, respectively. Examples include (but are not limited to) methyl, ethyl, 1-propyl, isopropyl, 1-butyl, isobutyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neopentyl, and hexyl groups.

[0043] The term "C1-C6 alkoxy group" refers to a saturated straight or branched chain monovalent alkoxy group having from 1 to 6 carbon atoms, in which the bond is to the oxygen atom. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert-butoxy groups.

[0044] The terms "hydroxy C1-C6 alkyl-" and "hydroxy C2-C6 alkyl-" refer to saturated linear or branched monovalent alkyl groups having 1 to 6 or 2 to 6 carbon atoms, respectively, in which one carbon atom is substituted with a hydroxy group.

[0045] The terms "deuterated C1-C6 alkyl-", "halogen C1-C6 alkyl group", and "cyano C1-C6 alkyl group" refer to saturated linear or branched monovalent alkyl groups of one to six carbon atoms, respectively, in which one carbon atom is substituted with deuterium, halogen, or a cyano group.

[0046] The term "heterocycle" refers to a monocyclic or bicyclic non-aromatic heterocycle containing, in addition to carbon atoms, 2 to 4 heteroatoms selected from the group consisting of P and N atoms.

[0047] The term "aryl group" refers to an aromatic monocyclic or polycyclic group containing 6 to 19 carbon atoms. Aromatic groups include, but are not limited to, groups such as unsubstituted or substituted phenyl and unsubstituted or substituted naphthyl.

[0048] The terms "treating" or "treatment" referred to throughout this specification are used conventionally and refer to the management or care of an individual for the purpose of combating, alleviating, reducing, ameliorating or improving the condition of a disease or condition, such as cancer.

[0049] The term "individual" or "patient" includes organisms, e.g., humans and non-human animals, that can suffer from a cell proliferative disease or that can benefit from the administration of a compound of the invention. Preferred humans include human patients suffering from or susceptible to a cell proliferative disease or related condition described herein. The term "non-human animal" includes vertebrates, e.g., mammals such as non-human primates, sheep, cows, dogs, cats, and rodents (e.g., mice), as well as non-mammals such as chickens, amphibians, and reptiles.

[0050] The term "cell proliferation" includes anything involving unwanted or uncontrolled growth of cells. The compounds of the present invention can be used to prevent, inhibit, block, reduce, decrease, control, etc., cell proliferation and / or cell division, and / or the occurrence of apoptosis. The method comprises administering to an individual (including a mammal, including a human) in need thereof, a compound of the present invention or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, or solvate thereof, in an amount effective to treat or prevent the condition.

[0051] Compared with the prior art, the beneficial effects of the present invention are as follows: The CDK7 kinase inhibitor compounds of the present invention have superior enzymatic and cellular biological activities and better bioavailability than previously disclosed compounds of the same type, providing more options for novel antitumor drugs and showing promising future uses as drugs.

[0052] The present invention will be further explained in conjunction with the following examples, but the examples are not intended to limit the present invention in any way.

[0053] The following representative examples are intended to help explain the present invention and are not intended to, and should not be construed as, limiting the scope of the present invention. Indeed, the entire contents of the present document, including those appearing and described herein as well as the examples based on the technical literature and patents cited herein, and the various modifications and many further variations that have arisen therefrom, will be apparent to those skilled in the art. It should also be understood that the citation of these references serves to explain the contents of this specification. The following examples contain important supplementary information, examples, and guidelines that can be applied to various variations and similar cases in the present invention. [Example]

[0054] Example 1 The synthetic route for the compound of formula 8 of the present invention is as follows. [ka]

[0055] The method for producing the above compound 2 is as follows. [ka]

[0056] In a 100 mL round-bottom flask, compound 1 (2.0 g, 15.98 mmol) was dissolved in ethanol at room temperature, sodium ethanol (3.26 g, 47.9 mmol) and diethyl malonate (3.33 g, 20.8 mmol) were added, and the mixture was heated to 80 ° C (internal temperature) and stirred for 15 hours. After the reaction was completed, the mixture was cooled to room temperature, and 1 M HCl solution was added to adjust the pH to 2.0, causing a solid to precipitate. The solid was filtered and washed with water to obtain compound 2 as a white solid (2.8 g, 14.5 mmol) in a 91% yield.

[0057] The method for producing the above compound 3 is as follows. [ka]

[0058] A 100 mL round-bottom flask was taken, and 8 mL of phosphorus oxychloride and 7 mL of acetonitrile were added at room temperature. 2 (500 mg, 2.6 mmol) was then slowly added to the reaction mixture. The reaction mixture was then added dropwise to triethylamine (521.13 mg, 5.2 mmol) at 0 °C. After the addition was complete, the reaction temperature was raised to 90 °C and stirred overnight until the raw materials had completely reacted. After the reaction was complete, the reaction mixture was concentrated, and the reaction mixture was quenched by slowly adding it dropwise to ice water. The pH was adjusted to basic with solid sodium bicarbonate, and the mixture was extracted with methyl tert-butyl ether. The organic phase was concentrated to obtain crude product 3 as a reddish-brown solid.

[0059] The method for producing the above compound 4 is as follows. [ka]

[0060] Compound 3 (500 mg, 2.17 mmol), deuterated benzylamine (521.02 mg, 4.78 mmol), and triethylamine (439.2 mg, 4.34 mmol) were dissolved in ethanol in a 100 mL round-bottom flask at room temperature. The mixture was refluxed overnight until the starting materials were completely reacted. After the reaction was completed, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to obtain compound 4 (491.5 mg, 1.64 mmol) in a 78% yield.

[0061] The method for producing the above compound 5 is as follows. [ka]

[0062] A 100 mL round-bottom flask was used. 4 (491.5 mg, 1.64 mmol) and BoCO (465.3 mg, 2.13 mmol) were added to the flask at room temperature. The mixture was stirred in THF for 2 hours until the raw materials were completely reacted. After the reaction was completed, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to obtain compound 5 (616.2 mg, 1.54 mmol) in a 94.3% yield.

[0063] The method for producing the above compound 7 is as follows. [ka]

[0064] A 100 mL round-bottom flask was used. 5 (500 mg, 1.25 mmol), Pd2dba3 (114.4 mg, 0.125 mmol), BINAP (233.5 mg, 0.38 mmol), and sodium tert-butoxide (180.2 mg, 1.88 mmol) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 5 min. 6 (345 mg, 1.5 mmol) was then slowly added to the reaction mixture. The mixture was then heated to 95 °C and refluxed overnight. After TLC showed no remaining starting material, the reaction mixture was extracted with water and ethyl acetate. The combined organic phases were separated by column chromatography (PE:EA = 1:1) to give the final product 7 (370 mg, 0.62 mmol) in 50% yield.

[0065] The method for producing the above compound 8 is as follows. [ka]

[0066] A 100 mL round-bottom flask was taken, and 7 (370 mg, 0.62 mmol) was slowly added dropwise to 30 mL of ethyl acetate hydrochloride, and the mixture was stirred at room temperature for 2 hours until the raw materials were completely reacted. The mixture was separated by thin-layer chromatography to obtain the final product 8 (98 mg, 0.24 mmol), with a yield of 40%. 1H NMR (400 MHz, Chloroform-d) δ 7.65 (s, 1H), 7.39-7.30 (m, 5H), 6.46 (s, 1H), 4.98 (s, 1H), 4.80-4.71 (m, 1H), 4.30 (ddd, J = 14.8, 8.1, 2.9 Hz, 1H), 3.22 (ddd, J = 20.9, 10.5, 4.9 Hz, 2H), 3.13-2.98 (m, 2H), 2.92 (ddd, J = 14.6, 5.6, 1.8 Hz, 1H), 2.58 (td, J = 12.0, 2.8 Hz, 1H), 2.48 (t, J = 10.7 Hz, 1H), 1.60-1.41 (m, 3H), 1.29 (dd, J = 9.3, 6.9 Hz, 6H). LC-MS [M+H + ]397.37.

[0067] Example 2 The synthetic route for the compound of formula 22 of the present invention is as follows. [ka]

[0068] The method for producing the above compound 17 is as follows. [ka]

[0069] In a 100 mL round-bottom flask, 16 (2.0 g, 18.5 mmol) was dissolved in ethanol at room temperature, and sodium ethanol (3.78 g, 55.5 mmol) and diethyl malonate (3.85 g, 1.3 mmol) were added. The mixture was heated to 80°C (internal temperature) and stirred for 15 hours. After the reaction was completed, the mixture was cooled to room temperature and the pH was adjusted to 2.0 by adding 1 M HCl solution. A solid precipitated, which was filtered and washed with water to obtain compound 17 as a white solid (1.7 g, 9.6 mmol) in a 52% yield.

[0070] The method for producing the above compound 18 is as follows. [ka]

[0071] A 100 mL round-bottom flask was taken, and 25 mL of phosphorus oxychloride and 24 mL of acetonitrile were added at room temperature. 17 (1.7 g, 9.66 mmol) was then slowly added to the reaction mixture. Triethylamine (1.96 g, 19.32 mmol) was then added dropwise at 0 °C. After the addition was complete, the reaction temperature was raised to 90 °C and stirred overnight until the starting materials were completely reacted. After the reaction was complete, the reaction mixture was concentrated, and the reaction mixture was quenched by slowly adding it dropwise to ice water. The pH was adjusted to basic with solid sodium bicarbonate, and the mixture was extracted with methyl tert-butyl ether. The organic phase was concentrated to give crude product 18 (1.2 g, 5.69 mmol) as a reddish-brown solid in 59% yield.

[0072] The method for producing the above compound 19 is as follows. [ka]

[0073] A 100 mL round-bottom flask was used. 18 (1.2 g, 5.69 mmol), benzylamine (1.34 g, 12.5 mmol), and triethylamine (2.02 g, 11.38 mmol) were dissolved in ethanol at room temperature and refluxed overnight until the starting materials were completely reacted. After the reaction was completed, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to give compound 19 (1.3 g, 4.5 mmol) in 79% yield.

[0074] The method for producing the above compound 20 is as follows. [ka]

[0075] A 100 mL round-bottom flask was used. 19 (1.3 g, 4.5 mmol), BoCO (5.1 g, 23.4 mmol), and DMAP (114.5 mg, 0.9 mmol) were dissolved in THF and stirred at room temperature for 12 hours until the reaction was complete. After completion of the reaction, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to obtain compound 20 (1.6 g, 4.23 mmol) in a 94% yield.

[0076] The method for producing the above compound 21 is as follows. [ka]

[0077] A 100 mL round-bottom flask was used. 20 (400 mg, 1.04 mmol), Pd2dba3 (95.16 mg, 0.11 mmol), BINAP (194.28 mg, 0.312 mmol), and sodium tert-butoxide (151.36 mg, 1.58 mmol) were dissolved in toluene (20 mL). The mixture was stirred at room temperature for 5 min. 6 (288.3 mg, 1.25 mmol) was then slowly added to the reaction mixture. The mixture was then heated to 95 °C and refluxed overnight. After TLC showed no remaining starting material, the reaction mixture was extracted with water and ethyl acetate. The combined organic phases were separated by column chromatography (PE:EA = 1:1) to give the final product 21 (277.8 mg, 0.58 mmol) in 56% yield.

[0078] The method for producing the above compound 22 is as follows. [ka]

[0079] A 100 mL round-bottom flask was used, and 21 (277.8 mg, 0.58 mmol) was added in portions to a solution of hydrochloric acid and ethyl acetate. The mixture was stirred at room temperature for 2 hours until the raw materials were completely reacted and aqueous ammonia was liberated. The mixture was extracted with ethyl acetate, and the organic phases were combined and separated by column chromatography to obtain 45 mg of product 22. 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.28 (s, 1H), 7.47 (s, 1H), 7.39-7.32 (m, 4H), 7.27 (dd, J = 8.0, 5.0 Hz, 1H), 5.57 (s, 1H), 5.41 (s, 1H), 4.46 (s, 2H), 3.68-3.47 (m, 2H), 3.16 (td, J = 16.1, 14.1, 8.1 Hz, 3H), 2.65 (dt, J = 53.2, 11.6 Hz, 2H), 1.63 (d, J = 9.9Hz, 2H), 1.52-1.15 (m, 3H). LC-MS [M+H + ]378.34.

[0080] Example 3 The synthetic route for the compound of formula 33 of the present invention is as follows. [ka]

[0081] The compound 30 can be produced as follows. [ka]

[0082] A 100 mL round-bottom flask was used. 3 (500 mg, 2.17 mmol), propargylamine (119.5 mg, 2.17 mmol), and DIPEA (336.7 mg, 2.6 mmol) were dissolved in isopropanol at room temperature. The mixture was then allowed to react overnight at room temperature until the starting materials were completely reacted. After the reaction was complete, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to give compound 30 (468.2 mg, 1.89 mmol) in 87% yield.

[0083] The method for producing the above compound 31 is as follows. [ka]

[0084] A 100 mL round-bottom flask was used. 30 (468.2 mg, 1.89 mmol), BoCO (536.2 mg, 2.46 mmol), and DMAP (22 mg, 0.18 mmol) were dissolved in THF and stirred at room temperature for 2 hours until the starting materials were completely reacted. After the reaction was complete, the reaction mixture was evaporated to dryness and separated by column chromatography (PE:EA = 10:1) to give compound 31 (618.3 mg, 1.78 mmol) in 94% yield.

[0085] The method for producing the above compound 32 is as follows. [ka]

[0086] In a 100 mL round-bottom flask, 31 (618.3 mg, 1.78 mmol), 6 (409.4 mg, 1.78 mmol), and DIPEA (460.3 mg, 3.56 mmol) were dissolved in DMAC and then heated to 130 °C and refluxed overnight. After TLC confirmed that no raw materials remained, the reaction mixture was extracted with water and ethyl acetate. The combined organic phases were separated by column chromatography (PE:EA = 3:1) to give the final product 32 (646.38 mg, 1.19 mmol) in 67% yield.

[0087] The method for producing the above compound 33 is as follows. [ka]

[0088] A 100 mL round-bottom flask was used to prepare a 3 mol / L methanesulfonic acid / dry dichloromethane solution. 32 (646.38 mg, 1.19 mmol) was added to the reaction mixture in several portions. The mixture was stirred at room temperature for 2 hours until the raw materials were completely reacted and saturated potassium carbonate solution was released. The mixture was extracted with dichloromethane, and the organic phases were combined and subjected to high-pressure preparative chromatography to obtain 48 mg of product 33. 1 H NMR (400 MHz, Chloroform-d) δ 7.72-7.57 (m, 1H), 6.34 (s, 1H), 5.52 (s, 1H), 5.27 (s, 1H), 4.25 (s, 1H), 3.99 (d, J = 30.0 Hz, 2H), 3.39-3.33 (m, 1H), 3.28-3.16 (m, 2H), 3.08-2.96 (m, 2H), 2.74-2.57 (m, 2H), 2.34 (dd, J = 22.7, 2.5 Hz, 1H), 1.55 (dd, J = 26.2, 11.9 Hz, 3H), 1.28-1.23 (m, 6H). LC-MS [M+H + ]343.30.

[0089] Example 4 The synthetic route for the compound of formula 38 of the present invention is as follows. [ka]

[0090] The compound 34 can be prepared as follows. [ka]

[0091] Compound 3 (1.05 g, 4.56 mmol) and aqueous ammonia (25%) (10.86 g, 77.5 mmol) were accurately weighed and added sequentially to a 75 mL sealed tube. The tube was sealed, and the temperature was controlled at 80° C. to react for 6 hours.

[0092] LC-MS confirmed that the starting material had completely reacted. The mixture was cooled to room temperature and stirred at 0 °C for 15 minutes to precipitate more solids. The mixture was filtered under suction, and the filter cake was rinsed with water and then dried under suction. The filter cake was dissolved in methyl tert-butyl ether, the aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under vacuum. 34 (0.8 g, 3.80 mmol) was obtained as an off-white solid in 83.3% yield.

[0093] The method for producing the above compound 35 is as follows. [ka]

[0094] Compound 34 (610 mg, 2.9 mmol), THF (6.0 g), BocO (664 mg, 3.05 mmol), triethylamine (293 mg, 2.9 mmol), and 4-dimethylaminopyridine (DMAP) (35 mg, 0.29 mmol) were accurately weighed and added in order to a 100 mL single-neck flask and allowed to react at room temperature for 4 hours.

[0095] After the reaction of the starting material was confirmed by TLC, the reaction mixture was desolvated under vacuum, and the residue was dissolved in a small amount of dichloromethane and purified by column chromatography (PE:EA=20:1) to give compound 35 (800 mg, 2.58 mmol) as a white solid in a yield of 88.9%.

[0096] The method for producing the above compound 36 is as follows. [ka]

[0097] Compound 35 (400 mg, 1.29 mmol), ACN (4.0 g), 1-bromo-2-butyne (189 mg, 1.42 mmol), and cesium carbonate (463 mg, 1.42 mmol) were accurately weighed and added in order to a 15 mL sealed tube. The temperature was controlled at 80°C and the reaction was carried out for 2 hours.

[0098] After TLC showed that the starting material had completely reacted, the reaction mixture was cooled to room temperature, filtered, and the filter cake was rinsed with DCM and dried under vacuum. The filtrate was desolvated under vacuum. The residue was dissolved in a small amount of dichloromethane and purified by column chromatography (PE:EA=20:1) to give 36 (450 mg, 1.24 mmol) as a white solid in 96.3% yield.

[0099] The method for producing the above compound 37 is as follows. [ka]

[0100] Compound 36 (400 mg, 1.1 mmol), dimethylacetamide (4.0 g), compound 6 (330 mg, 1.43 mmol), and DIPEA (427 mg, 3.3 mmol) were accurately weighed and added in order to a 15 mL sealed tube. The tube was sealed under argon gas protection, and the temperature was controlled at 130°C for 20 hours.

[0101] After TLC showed the complete reaction of the starting material, the mixture was cooled to room temperature, poured into water, and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography with gradient elution (PE:EA = 5:1 → 3:1 → 2:1) to give 37 (510 mg, 1.07 mmol) as a pale yellow liquid in 97.8% yield.

[0102] The compound 38 can be prepared as follows. [ka]

[0103] Compound 37 (510 mg, 0.917 mmol), dry DCM (5 mL) and methanesulfonic acid (528 mg, 5.5 mmol) were accurately weighed and added in order to a 25 mL single-neck flask, and the reaction was carried out at room temperature for 3 hours under argon gas protection.

[0104] LC-MS confirmed that the starting material and the intermediate (one Boc group had been removed) had completely reacted. The reaction mixture was poured into saturated sodium bicarbonate solution, and the pH of the aqueous phase was measured at 8-9. Extraction was performed three times with EA, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. A small amount of diethyl ether was added to the residue to precipitate a solid. The mixture was stirred at room temperature for 15 minutes, suction filtered, and the filter cake was dried under vacuum.

[0105] A pale yellow solid 38 (75 mg) was obtained, a yield of 23%. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 6.20 (s, 1H), 5.17 (s, 1H), 4.91 (t, J = 6.9 Hz, 1H), 4.36 (ddd, J = 14.8, 7.9, 3.3 Hz, 1H), 4.01 (s,2H), 3.55 (td, J = 10.4, 3.8 Hz, 1H), 3.49 (t, J = 7.0 Hz, 1H), 3.41 (dd, J = 11.9, 4.5 Hz, 1H), 3.33 (d, J = 12.4 Hz, 1H), 3.16-2.98 (m, 2H), 2.74 (td, J = 12.4, 3.3 Hz, 1H), 2.65 (t, J = 11.4 Hz, 1H), 1.83 (t, J = 2.4 Hz, 3H), 1.79-1.65 (m, 2H), 1.59 (d, J = 11.3 Hz, 1H), 1.30 (dd, J = 11.4, 6.9 Hz, 6H).

[0106] Example 5 The synthetic route for the compound of formula 41 of the present invention is as follows. [ka]

[0107] The method for producing the above compound 39 is as follows. [ka]

[0108] Compound 35 (300 mg, 0.97 mmol), ACN (4.0 g), allyl bromide (130 mg, 1.07 mmol), and cesium carbonate (350 mg, 1.07 mmol) were accurately weighed and added in order to a 15 mL sealed tube. The temperature was controlled at 80°C and the reaction was carried out for 2 hours.

[0109] After TLC showed the complete reaction of the starting material, the reaction mixture was cooled to room temperature, filtered under vacuum, and the filter cake was rinsed with DCM and dried under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA = 20:1) to give 39 (303 mg, 0.869 mmol) as a white solid in 89.6% yield.

[0110] The method for producing the above compound 40 is as follows. [ka]

[0111] Compound 39 (300 mg, 0.86 mmol), DMAc (5.0 g), compound 6 (256 mg, 1.12 mmol), and DIPEA (333 mg, 2.58 mmol) were accurately weighed and added sequentially to a 15 mL sealed tube. The tube was sealed under argon gas protection, and the temperature was controlled at 130°C for 7 hours.

[0112] After TLC showed the complete reaction of the starting materials, the mixture was cooled to room temperature, poured into water, and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography with gradient elution (PE:EA = 4:1 → 2.5:1) to give 40 (350 mg) as a pale yellow liquid in 75.1% yield.

[0113] The method for producing the above compound 41 is as follows. [ka]

[0114] Compound 40 (300 mg, 0.643 mmol), dry DCM (4 mL), and methanesulfonic acid (370 mg, 3.86 mmol) were accurately weighed and added sequentially to a 25 mL single-neck flask, and the reaction was carried out at room temperature under argon gas protection for 3 hours.

[0115] LC-MS confirmed that the starting material and the intermediate (one Boc group removed) were completely reacted. The reaction mixture was poured into saturated sodium bicarbonate solution, and the pH of the aqueous phase was measured at 8-9. Extraction was performed three times with EA, and the organic phases were combined. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. A small amount of diethyl ether was added to the residue to precipitate a solid. The solid was stirred at room temperature for 15 minutes, suction filtered, and the filter cake was removed. The filter cake was dried under vacuum to give a pale yellow solid, 41 (68 mg), in a 30% yield. 1 H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 6.19 (d, J = 6.4 Hz, 1H), 5.91 (tt, J = 10.6, 5.3 Hz, 1H), 5.30 (dd, J = 30.8, 13.8 Hz, 2H), 5.02 (s, 1H), 4.71 (s, 1H), 4.38 (dd, J = 14.3, 8.4 Hz, 1H), 3.92 (s, 2H), 3.53-3.18 (m, 2H), 3.16-3.02 (m, 2H), 2.97 (dd, J = 14.7, 5.3 Hz, 1H), 2.57 (dt, J = 43.4, 11.3 Hz, 2H), 1.71-1.41 (m, 3H), 1.31 (d, J = 7.6 Hz, 6H).

[0116] Example 6 The synthetic route for the compound of formula 45 of the present invention is as follows. [ka]

[0117] The method for producing the above compound 42 is as follows. [ka]

[0118] Compound 3 (500 mg, 2.17 mmol), ethanol (6 g), cyclopropylmethylamine (300 mg, 4.34 mmol), and triethylamine (438 mg, 4.34 mmol) were accurately weighed and added sequentially to a 15 mL sealed tube. The tube was sealed, and the temperature was controlled at 80°C for 3 hours to react.

[0119] LC-MS showed that the starting material had reacted completely, and the reaction mixture was desolvated under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA=20:1) to give 42 (490 mg, 1.86 mmol) as an off-white solid in 85.5% yield.

[0120] The method for producing the above compound 43 is as follows. [ka]

[0121] Compound 42 (490 mg, 1.85 mmol), THF (4.0 g), BocO (484 mg, 2.22 mmol), TEA (280 mg, 2.78 mmol), and DMAP (23 mg, 0.19 mmol) were accurately weighed and added in order to a 100 mL single-neck flask and allowed to react at room temperature for 20 hours.

[0122] After the reaction of the starting material was confirmed by TLC, the reaction mixture was desolvated under vacuum, and the residue was dissolved in a small amount of DCM and purified by column chromatography (PE:EA=30:1) to give 43 (600 mg, 1.64 mmol) as a pale yellow oil in 88.9% yield.

[0123] The method for producing the above compound 44 is as follows. [ka]

[0124] Compound 43 (600 mg, 1.66 mmol), DMAc (6.0 g), compound 6 (492 mg, 2.14 mmol), and DIPEA (638 mg, 4.93 mmol) were accurately weighed and added in order to a 75 mL sealed tube. The tube was sealed under argon gas protection, and the temperature was controlled at 130°C for 4 hours to react.

[0125] After TLC showed the complete reaction of the starting materials, the mixture was cooled to room temperature, poured into water, and extracted three times with EA. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography with gradient elution (PE:EA = 4:1 → 2:1) to give 44 (680 mg, 1.23 mmol) as a pale yellow liquid in 73.9% yield.

[0126] The method for producing the above compound 45 is as follows. [ka]

[0127] Compound 44 (100 mg, 0.18 mmol), ethyl acetate (1 mL), and hydrochloric acid / ethyl acetate (3 M) (3 mL, 9 mmol) were accurately weighed and added sequentially to a 25 mL single-neck flask, and the reaction was carried out at room temperature for 6 hours under argon gas protection.

[0128] LC-MS confirmed that the starting material and the intermediate (one Boc group removed) were completely reacted. The reaction mixture was poured into saturated sodium bicarbonate solution, and the pH of the aqueous phase was measured at 8-9. Extraction was performed three times with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was stripped under vacuum. The residue was dissolved in a small amount of DCM and purified by column chromatography using gradient elution (DCM:MeOH = 10:1 → 5:1 → 4:1) to give 45 (33 mg, 0.09 mmol) as an off-white solid in 51.6% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.67 (s, 1H), 6.10 (s, 1H), 5.02 (s, 1H), 4.72 (dd, J = 8.2, 5.5 Hz, 1H), 4.38 (ddd, J = 14.9, 8.2, 2.6 Hz, 1H), 3.31 (td, J = 11.0, 9.5, 4.4 Hz, 1H), 3.25 (dd, J = 11.4, 4.5 Hz, 1H), 3.15-3.05 (m, 4H), 2.97 (dd, J = 14.6, 5.4 Hz, 1H), 2.70-2.60 (m, 1H), 2.54 (t, J = 10.8 Hz, 1H), 1.68-1.59 (m, 1H), 1.57-1.51 (m, 2H), 1.39 (s, 1H), 1.35-1.23 (m, 6H), 0.70-0.56 (m, 2H), 0.32 (q, J = 5.2 Hz, 2H). LC-MS: [M+H] + = 359.43,[M+2H] 2+ / 2= 180.30.

[0129] Biological Activity Tests The following assay method was used to biologically assay a known CDK inhibitor (CT7001, developed and prepared by Emory University) and the compound prepared in the present invention, and demonstrated that the compound prepared in the present invention has CDK7 kinase activity inhibitory activity and has superior biological activity at the enzyme and cellular levels to previously disclosed compounds of the same type.

[0130] Study 1: ICR mouse PK experiment Male ICR mice (18-20 g body weight) were administered 10 mg / kg of the known CDK inhibitor CT7001 and compounds 33 and 41 of the present invention via intragastric administration and tail vein injection, respectively. Each group consisted of 12 animals. The administration vehicle was 10% DMSO + 10% polyoxyethylene castor oil + 80% saline solution. The intragastric administration group was fasted for approximately 12 hours before administration and fed simultaneously 4 hours after administration. Water was not permitted throughout the experiment. Approximately 0.2 mL of blood was collected via the orbit before administration and at 5, 15, and 30 minutes, and at 1, 2, 4, 6, 8, and 24 hours after administration. The blood was placed in an EDTA-K2 anticoagulated EP tube, placed on ice, and centrifuged at 3500 rpm for 5 minutes at 4°C to separate plasma. Plasma centrifugation was completed within 1 hour of collection, and plasma samples were stored at -20°C until analysis. Plasma concentrations of CT7001, 33, and 41 were quantitatively analyzed by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Pharmacokinetic parameters were calculated using WinNonlin software.

[0131] As can be seen from the data in Table 1, compound 41 prepared in the present invention has better bioavailability than CT7001 after oral administration.

[0132] [Table 1]

[0133] [Table 2]

[0134] As can be seen from the data in Table 2, compound 33 prepared in the present invention has a longer half-life than CT7001 after intravenous administration, allowing for reduced administration frequency. Compounds 33 and 41 have a higher steady-state apparent volume of distribution (Vss) in mice after intravenous administration, resulting in wider distribution of the drug in tissues.

[0135] Test 2: Detection of inhibition of CDK7 / CycH / MAT1 enzyme activity by the manufactured compounds The CDK7 / CycH / MAT1 protein was thawed on ice, and the remaining reagents were equilibrated to room temperature. The CDK7 / CycH / MAT1 protein and ATP / substrate were adjusted to the corresponding concentrations using enzyme reaction buffer (50 mM Hepes, 10 mM MgCl2, 0.01% Brij35, 1 mM EGTA, 2 mM DTT). Test compounds were added to a 384-well white-walled low-volume microplate at 20 nL per well, followed by the addition of the prepared CDK7 / CycH / MAT1 protein (2 μL / well). The mixture was mixed evenly and incubated at 25°C for 10 minutes. The reaction was then initiated by the addition of ATP / substrate and allowed to proceed at 25°C for 60 minutes. The concentrations of each reaction component in the enzyme reaction system were 3.5 ng / μL CDK7 / CycH / MAT1 protein, 30 μM ATP, and 0.1 μM substrate. The test compound concentrations, in descending order, were 5000, 1667, 556, 185, 62, 21, 7, 2, 1, and 0.3 nM. After the enzyme reaction was completed, 4 μL of ADP-Glo ​​Reagent was added to each well and incubated at 25°C for 40 minutes. Then, 8 μL of Kinase Detection Reagent was added to each well and incubated at 25°C for 40 minutes. The chemiluminescence signal was recorded using a plate reader, and the curve was plotted to determine the IC. 50 values ​​were calculated.

[0136] As shown by the data in Table 3, compounds 8, 22, 33, and 41 exhibited IC 50 All of the values ​​were less than 10 nM, and the compounds prepared according to the present invention have an inhibitory effect on CDK7 / CycH / MAT1 kinase activity.

[0137] [Table 3]

[0138] Test 3: Test for inhibition of tumor cell growth by compounds Cells were cultured in the corresponding growth medium, and tumor cell lines, including HCT-116, MDA-MB-468, Jurkat, HCC70, and MDA-MB-436, were seeded into 384-well plates at 600, 300, 800, 800, and 1000 cells / well (18 μL / well), respectively, and then incubated overnight at 37°C and 5% CO2 (MDA-MB-468 was incubated overnight at 37°C and 100% air). A 10 mM working solution of test samples was prepared in DMSO, and a 10x intermediate dilution plate was prepared by diluting 10 samples 1:3 in 1% DMSO. Cell plates were treated by adding 2 μL / well from the 10x intermediate dilution plate to the cell plates to achieve the final experimental concentrations (10,000, 3,333, 1,111, 370, 123, 41, 14, 4.6, and 1.5 nM). HCT-116, Jurkat, and HCC70 cell plates were incubated at 37°C, 5% CO2 for 3, 7, and 7 days, respectively (MDA-MB-468 cell plates were incubated at 37°C, 100% air for 7 days). After treatment, the CellTiter-Glo reagent was removed from -20°C and equilibrated to room temperature. Cell Titer-Glo reagent (20 μL / well) was added to the cell plate and incubated for 10 minutes. After 10 minutes, luminescence was read using a plate reader. Data were analyzed using Excel, and relevant calculations were performed using Graph Pad Prism 7.0 software. The table shows the IC values ​​for tumor cell growth inhibition by compounds. 50 The values ​​are shown.

[0139] As can be seen from the data in Table 4, 41 had a stronger inhibitory effect on tumor cell proliferation than CT7001 in all tumor cell types tested.

[0140] [Table 4]

[0141] It should be noted that the above is merely a preferred embodiment of the present invention, and those skilled in the art may make some improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of the claims of the present invention.

Claims

1. A compound of the structure of formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, or prodrug thereof, 【Chemistry 1】 In the formula, R １ is a substituted or unsubstituted deuterated C1-C3 alkyl group, a C1-C3 alkyl group, a C2-C6 olefin, a C2-C6 alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group; the substituents are independently selected from H, D, halogen, a hydroxy group, —CN, a carbonyl group, a C1-C3 alkyl group, a C2-C3 olefin, a C2-C3 alkyne, a deuterated C1-C3 alkyl group, a C1-C3 alkoxy group, a hydroxy C1-C3 alkyl group, a fluoro C1-C3 alkyl group, a cyano C1-C3 alkyl group, a C3-8 cycloalkyl group, a C3-10 heterocyclyl group, and a C6-10 aryl group; R ２ is selected from halogen, a hydroxy group, —CN, a carbonyl group, a C1 to C3 alkyl group, a C2 to C3 olefin or alkyne, a deuterated C1 to C3 alkyl group, a C1 to C3 alkoxy group, a hydroxy C1 to C3 alkyl group, a fluoro C1 to C3 alkyl group, and a cyano C1 to C3 alkyl group; R １ is a benzyl group, R ２ is -CN, A compound or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, or prodrug thereof.

2. R １ is a substituted or unsubstituted C1-C3 alkyl group, a C2-C6 olefin or alkyne, or a substituted or unsubstituted C6-10 aryl C1-6 alkyl group, or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof.

3. R ２ The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, wherein is selected from -CN, a C1-C3 alkyl group.

4. R １ is substituted or unsubstituted 【Chemistry 2】 2. The compound of claim 1, wherein:

5. The compound is 【Transformation 3】 2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug thereof, selected from:

6. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, or prodrug thereof.

7. 7. The pharmaceutical composition of claim 6, further comprising another therapeutic agent and / or a pharmaceutically acceptable carrier.

8. Use of the compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, or prodrug thereof, or the pharmaceutical composition of claim 6 in the manufacture of a CDK kinase inhibitor.

9. Use of a compound of claim 1 or a pharmaceutically acceptable salt, ester, stereoisomer, solvate, prodrug thereof, or a pharmaceutical composition of claim 6 in the manufacture of a medicament for treating and / or inhibiting a CDK-related disease.

10. The use according to claim 9, characterized in that the CDK-related disease is cancer.

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